Inflammation Remodels the Immune Microenvironment in Acute Myeloid Leukemia

Audrey Lasry ¹ Bettina Nadorp ^1,2 Maarten Fornerod ³ Deedra Nicolet ^4,5 Huiyun Wu ⁶ Christopher J. Walker ^4,5 Zhengxi Sun ¹ Matthew T Witkowski ¹ Anastasia N. Tikhonova ¹ Maria Guillamot-Ruano ¹ Geraldine Cayanan ¹ Anna Yeaton ¹ Gabriel Robbins ¹ Esther Obeng ⁷ Aristotelis Tsirigos ^1,2 Richard M. Stone ⁸ John C. Byrd ⁹ Stanley Pounds ⁶ William L. Carroll ¹ Tanja A. Gruber ¹⁰ Ann-Kathrin Eisfeld ^4,11 Iannis Aifantis ¹

¹Department of Pathology, NYU Grossman Schoold of Medicine, USA
²Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, USA
³Department of Cell Biology, Erasmus Medical Center, Netherlands
⁴Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University Comprehensive Cancer Center, USA
⁵Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, USA
⁶Department of Biostatistics, St. Jude Children’s Research Hospital, USA
⁷Department of Oncology, St. Jude Children’s Research Hospital, USA
⁸Department of Medical Oncology, Dana-Farber Cancer Institute, USA
⁹Department of Internal Medicine, University of Cincinnati, USA
¹⁰Department of Pediatrics, Stanford University School of Medicine, USA
¹¹Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, USA

Acute myeloid leukemia (AML) is a hematopoietic malignancy with a poor prognosis and limited treatment options. Efforts to target the AML immune microenvironment have yielded modest clinical benefits. Here we provide a comprehensive census of the bone marrow immune microenvironment in adult and pediatric AML patients, distinguishing malignant and non-malignant cells. We characterize unique inflammation signatures highly expressed in the malignant cells of a subset of AML patients, associated with inferior treatment outcomes. This inflammatory microenvironment is associated with alterations in lymphoid populations. Specifically, we identify atypical B cells, a dysfunctional B cell subtype enriched in high-inflammation AML patients, as well as an increase in CD8+ GZMK+ T cells and regulatory T cells accompanied by a reduction in T cell clonal expansion. Combined, these data suggest that a subset of patients have inflammatory immune microenvironments that blunt the anti-tumor immune response. An inflammation-associated gene expression score (iScore) was derived that associates with survival outcomes in both adult and pediatric patients. The addition of the iScore refined currently utilized risk stratifications for both adult and pediatric patients and may enable identification of patients in need of more aggressive treatment approaches. Overall, this work provides a first framework for classifying AML patients based on their immune microenvironment and provides a rationale for consideration of the inflammatory state in the clinical setting.